Repair of the Degenerated Disc: A Perspective Derived from Cell-Based Studies

Abstract

Like articular joints, intervertebral discs (IVD) suffer from degeneration which is thought to be irreversible after initiation. Disc degeneration is associated with low back pain, and the degenerative IVD can be a source of irritation. While the cause of IVD degeneration is not entirely understood to date, both genetic and environmental factors have shown contribution to its etiology. Various studies investigated disc repair or regeneration via cell-based approaches. These findings help us to derive new insights or principles about the degeneration, and the use of related therapies in future. Nucleus pulposus (NP) has a role in disc height maintenance and supporting motion of spinal segment. The loss of NP integrity is one of the earliest events of disc degeneration, implying a critical function of NP in IVD homeostasis. Recovery of the NP function is therefore an important goal in treating disc degeneration. Transplantation of chondrocytes or NP cells has shown some extent of reparative capacity. Nevertheless, the use of mesenchymal stromal/stem cells (MSCs) in treating IVD degeneration has drawn much attention in the last decade. Studies have attempted to engineer MSCs into NP-like cells directly for de novo disc engineering or disc implantation, aiming to restore the matrix and hence recover the native NP function. This includes the use of growth factors such as TGF-beta, GDFs, and BMPs to induce MSC differentiation in vitro. MSCs may also be delivered directly into the disc where the engrafted MSCs acquire a differentiated phenotype to benefit NP function. Results from pilot clinical trials support that intradiscal MSC implantation may alleviate symptoms and possibly delay IVD degeneration progression. While the use of models and regime of MSC introduction may vary, the results from the in vivo studies have laid important foundation to our understanding in the capacity and mechanism of MSC-based therapies. One school of thoughts is that MSCs can attain a collage II and proteoglycan expressing phenotype in the degenerated discs. However, other reports have also suggested that MSCs and NP cells can mutually exchange biological information and promote anabolic activities through cell-cell contact or paracrine action. Therefore MSCs may contribute to disc repair via pathways other than direct differentiation. MSCs may have other capacities in alleviating disc degeneration. Autopsy and surgical specimens show evidence of fibrosis in the majority of degenerated discs. We recently show that human IVD degeneration exhibits features of fibrosis and that a rabbit disc degeneration model shows similar features. Implantation of bone marrow-derived MSCs can inhibit fibrosis-related events in the degenerative NP and effectively preserves its mechanical characteristics and the overall motion segment function. MSCs may achieve this by repressing the profibrotic mediators that are implicated in mediating collagen anomalies in fibrotic diseases. Altogether, these support a model where MSCs may have a capacity in actively modifying the local microenvironment to potentiate resident progenitor function for tissue repair. Disclosures: None